CN102775515A - Amphiphilic chitosan derivatives, and preparation method and application thereof - Google Patents
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Abstract
The invention discloses amphiphilic chitosan derivatives, and a preparation method and application thereof. The structural formula is diclosed as Formula I, wherein M represents a hydrophobic group, T represents a target ligand group, and n is 1200-4500; MCOOH is selected from at least one of deoxycholic acid, folic acid, hyaluronic acid, alanine, valine,, leucine, isoleucine, phenylalanine, tryptophane, tyrosine and proline; and TCOOH is selected from at least one of folic acid, epidermal growth factor, transferrin, nucleic acid aptamer, antibody and oligomer polypeptide. The chitosan derivatives disclosed by the invention can self-assemble into a micelle in a water solution, the hydrophobic core can be coated on the hydrophobic molecule, and the hydrophilic shell can specifically target the specific position through ligand modification. The particle size, medicine coating efficiency, drug loading efficiency and in-vivo drug release behavior of the micelle can be controlled by changing the hydrophilic group/hydrophobic group proportion. The derivatives have the advantages of mild and simple synthesis conditions, favorable biocompatibility and favorable biodegradability.
Description
Technical field
The present invention relates to a kind of amphipathic chitose derivative and preparation method thereof and application.
Background technology
At present, the multifunctional polymer micella that is used as pharmaceutical carrier mainly is the amphiphilic polymer molecule of good biocompatibility, utilizes their self-assemblies in the aqueous solution to obtain the stable micella of carrying function.Through the hydrophobic-hydrophobic interaction between drug molecule or image molecule and the micella molecule hydrophobic inner core, realize to functional molecular solubilising, transport and to the imaging spike of pathological tissues; On the other hand, carry out targeting modification through water-wet side and can realize the specific recognition of micella molecule, improve drug effect greatly, reduce toxic side effect, or realize high-resolution imaging, the sensitivity of raising disease detection of pathological tissues pathological tissues to the micella molecule.
Chitosan for the polymer micelle of representative owing to good biocompatibility, low in raw material cost are easy to get, biodegradable, synthetic modification simply receive extensive concern.Through on the chitosan skeleton, introducing hydrophilic group simultaneously and hydrophobic group carries out effective modification to chitosan; Utilize simultaneously simple amidate action with the target group bonding to the chitosan molecule skeleton; Not only can realize the solubilising of dewatering medicament is coated; And can also accomplish its target in vivo and transport, alleviate the toxic side effect of medicine to the full extent.Ratio through close and distant water base group in the regulation and control chitosan amphiphilic process can realize the accuracy controlling to micellar particle diameter, medicine coating efficiency and drug loading and inside and outside drug release behavior.
Summary of the invention
The purpose of this invention is to provide a kind of amphipathic chitose derivative and preparation method thereof and application.
Amphipathic chitose derivative provided by the present invention, its structural formula be suc as formula shown in the I,
The formula I
In the formula I, M representes hydrophobic grouping, and T representes the target ligand groups, and n is 1200 ~ 4500 number.
In the above-mentioned chitosan derivatives; Said M is selected from the M group among the MCOOH, and wherein said MCOOH can be selected from following at least a: Septochol, folic acid, mucinase, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine(Phe), tryptophane, tyrosine and proline(Pro).
In the above-mentioned chitosan derivatives, said T is selected from the T group among the TCOOH, and wherein said TCOOH can be selected from following at least a: folic acid, Urogastron, Transferrins,iron complexes, aptamer, antibody and oligomerization polypeptide.
The present invention further provides the preparation method of above-mentioned chitosan derivatives, comprises the steps:
(1) chitosan and MCOOH react under the condition of (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride (EDC) and N-hydroxy-succinamide (NHS) existence and obtain compound shown in the formula II;
Wherein, MCOOH is selected from Septochol, folic acid, mucinase, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine(Phe), tryptophane, tyrosine and the proline(Pro) at least a; N is 1200 ~ 4500 number;
The formula II
(2) compound and propylene oxide shown in the formula II react and obtain compound shown in the formula III;
The formula III
(3) compound and TCOOH shown in the formula III react under the condition that (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride exists and promptly get chitosan derivatives shown in the formula I;
Wherein, TCOOH is selected from folic acid, Urogastron, Transferrins,iron complexes, aptamer, antibody and the oligomerization polypeptide at least a.
Among the above-mentioned preparation method; In the step (1); The molfraction ratio of chitosan, MCOOH, (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide can be 1: (1000 ~ 4000): (500 ~ 2000): (1000 ~ 4000) specifically can be 1:1223:574:1043; The temperature of said reaction can be 20 ~ 50 ℃, and as 20 ℃, the time can be 15 ~ 25h, like 24h.
Among the above-mentioned preparation method, in the step (2), compound shown in the formula II is 1 with the molfraction ratio of propylene oxide: (10000 ~ 50000) specifically can be 1:31439; The temperature of said reaction is 20 ~ 50 ℃, and as 45 ℃, the time is 20 ~ 30h, like 24h; In the step (3), the molfraction ratio of compound shown in the formula III, T-COOH and (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride is 1: (3 ~ 300): (3 ~ 300) specifically can be 1:3.4:3.4; The temperature of said reaction is 20 ~ 50 ℃, and as 20 ℃, the time is 15 ~ 25h, like 16h.
The present invention also provides a kind of amphipathic chitose derivative micella; It can prepare according to following method: above-mentioned chitosan derivatives and hydrophobic molecule are dispersed in N; In the N-NMF, be added to then and promptly obtain the amphipathic chitose derivative micella that kernel is loaded with said hydrophobic molecule in the water.
In the above-mentioned verivate micella, said hydrophobic molecule can be hydrophobic drug and hydrophobic nano material.
In the above-mentioned verivate micella, said hydrophobic drug specifically can be selected from the following substances at least a: Zorubicin, taxol and NSC 94600; Said hydrophobic nano material specifically can be selected from the following substances at least a: SPIO nano particle, carbon nanotube and carbon nanometer bugle.
Chitosan derivatives provided by the invention can self-assembly form micella in the aqueous solution, its hydrophobic inner core can realize the coating to hydrophobic molecule, and its hydrophilic outer shell can pass through the ligand modified privileged site of target specifically.Micellar particle diameter, medicine coating efficiency and drug loading and inside and outside drug release behavior all can be regulated and control through the ratio that changes close and distant water base group.This verivate synthesis condition gentleness is easy, has excellent biological compatibility, biodegradable.The target that amphipathic chitose derivative of the present invention can also be applied to dewatering medicament and image molecule transports, and has wide practical use at numerous areas such as medicines and health protection, makeup.
Description of drawings
Fig. 1 is the absorption spectrum of the embodiment of the invention 1 synthetic amphipathic chitose derivative C1 in water.
Fig. 2 is the toxicity test result of the micellar solution M1 of the embodiment of the invention 2 synthetic amphipathic chitose derivative C1 to Hela cell and HBE cell.
Fig. 3 is the external release curve of micellar solution M2 in PBS5.8 and PBS7.4 solution that the embodiment of the invention 3 synthetic amphipathic chitose derivative C1 bag carries Zorubicin.
Fig. 4 is that amphipathic chitose derivative C1 bag carries the micellar solution M2 of Zorubicin and the growth-inhibiting curve of Zorubicin to Hela cell and HBE cell that dissociate in the embodiment of the invention 6; Growth-inhibiting superimposed curves when wherein, Fig. 4 a, Fig. 4 b and Fig. 4 c are respectively Hela cell and HBE cell cultures 24h, 48h and 72h.
Fig. 5 is the solution temperature rise curve that the amphipathic chitose derivative C1 bag of the embodiment of the invention 4 preparations carries the micellar solution M3 of single wall carbon nanometer bugle.
Fig. 6 is amphipathic chitose derivative C1 bag carries single wall carbon nanometer bugle in the embodiment of the invention 7 the micellar solution M3 growth-inhibiting result to the Hela cell after illumination.
Embodiment
Employed experimental technique is ordinary method like no specified otherwise among the following embodiment.
Used material, reagent etc. like no specified otherwise, all can obtain from commercial sources among the following embodiment.
(1) 100mL is dissolved with the 0.96g Septochol; 0.22g the methanol solution of EDC and 0.24g NHS is added drop-wise in 1% aqueous acetic acid that 100mL is dissolved with 1g chitosan (molecular weight is 500,000), under the room temperature behind the reaction 24h; Add 10mL methyl alcohol and ammoniacal liquor (7:3; V:v) mixed solution staticly settles, vacuum filtration.Repeatedly behind the washing precipitate, vacuum filtration is positioned over 50 ° of C vacuum-dryings in the vacuum drying oven with product with acetone, Septochol-chitosan; In the said process, the molfraction of chitosan, Septochol, EDC and NHS is than being 1:1223:574:1043.
(2), be scattered in the aqueous isopropanol that 30mL is dissolved with 0.8g NaOH alkalization 4h with the Septochol-chitosan that makes.Add the 4.4mL propylene oxide then, condensing reflux reaction 24h under 45 ° of C.After reaction finishes, the pH of reaction soln is transferred to neutrality with acetate, with washing with acetone for several times, vacuum filtration.Product is positioned over 50 ° of C vacuum-dryings in the vacuum drying oven, gets Septochol-hydroxypropyl chitosan; In the said process, Septochol-chitosan is 1:31439 with the molfraction ratio of propylene oxide.
(3) with the folic acid aqueous solution of 10mL 0.015mg/mL, the mixed solution of 1mL0.067mg/mL EDC and 89mL water dropwise adds under agitation condition and is equipped with in the three-necked flask of the above-mentioned Septochol-hydroxypropyl chitosan that makes of 50mg, reacts 16h under the room temperature.Product at 1000rpm ultrafiltration 20min to remove unreacted folic acid.With Rotary Evaporators the solution evaporate to dryness is promptly got amphipathic chitose derivative C1, i.e. Septochol-hydroxypropyl chitosan-folic acid, its structural formula is suc as formula shown in the I, and wherein, n is 3106; In the said process, the molfraction of Septochol-hydroxypropyl chitosan, folic acid and EDC is than being 1:3.4:3.4.
The absorption spectrum of C1 in water of present embodiment preparation is as shown in Figure 1.
The micellar solution M1 of embodiment 2, preparation amphipathic chitose derivative C1
Get 30mg Septochol-hydroxypropyl chitosan-folic acid C1, be dispersed among the 1mL DMSO, stir and after 2 hours the gained suspension is dropwise added in the 5mL deionized water; After continuing stirring reaction 10h, promptly get Septochol-hydroxypropyl chitosan-folic acid micellar solution M1.
Get 30mg Septochol-hydroxypropyl chitosan-folic acid C1 and 1mg Zorubicin, be dispersed among the 1mL DMSO, add 5 μ L triethylamines then, stir and after 2 hours the gained suspension is dropwise added in the 5mL deionized water; After continuing stirring reaction 10h, promptly get the Septochol-hydroxypropyl chitosan-folic acid micellar solution M2 that is loaded with Zorubicin.
The external release curve of M2 in PBS5.8 and PBS7.4 solution is as shown in Figure 2.
Embodiment 4, preparation amphipathic chitose derivative C1 bag carry the micellar solution M3 of single wall carbon nanometer bugle
Get 30mg Septochol-hydroxypropyl chitosan-folic acid C1 and 1mg single wall carbon nanometer bugle, be dispersed among the 1mL DMSO, behind the stirring 2h gained suspension is dropwise added in the 5mL deionized water; After continuing stirring reaction 10h, promptly get the Septochol-hydroxypropyl chitosan-folic acid micellar solution M3 that is loaded with single wall carbon nanometer bugle.
The solution temperature rise curve of M3 is as shown in Figure 5.
Recovery Hela cell and HBE cell, adjustment cell density to 5 * 10
4/ mL, with Hela cell and HBE cell kind in 96 orifice plates (7 * 6), at 37 ℃, 5%CO
2Hatch 24h under the condition, the M1DMEM solution of treating to change the different concns gradient into behind the cell attachment is at 37 ℃, 5%CO
2Continue to cultivate 24h, 48h and 72h under the condition.
According to operation instruction, detect Hela cell and HBE cell activity with cck-8, M1 is as shown in Figure 2 to the growth-inhibiting curve of Hela cell and HBE cell.
Embodiment 6, micellar solution M2 are applied to chemotherapy
Recovery Hela cell and HBE cell, adjustment cell density to 5 * 10
4/ mL, with Hela cell and HBE cell kind in 96 orifice plates (7 * 6), at 37 ℃, 5%CO
2Hatch 24h under the condition, the DMEM solution of M2 or free Zorubicin of treating to change into behind the cell attachment different concns gradient is at 37 ℃, 5%CO
2Continue to cultivate 24h, 48h and 72h under the condition.
According to operation instruction, detect Hela cell and HBE cell activity with cck-8, M2 or free Zorubicin are as shown in Figure 4 to the growth-inhibiting curve of Hela cell and HBE cell.
Embodiment 7, micellar solution M3 are applied to photo-thermal therapy
(1) recovery Hela cell, adjustment cell density to 5 * 10
4/ mL, with Hela cell kind in 96 orifice plates (4 * 4), at 37 ℃, 5%CO
2Hatched under the condition 24 hours, the M3DMEM solution of treating to change the different concns gradient into behind the cell attachment is at 37 ℃, 5%CO
2Continue to cultivate 24h under the condition.
(2) cell after will cultivating places that (power density is 1w/cm under the laser
2) irradiation 5min, every interval 30s recording solution temperature.
(3) discard DMEM substratum after the illumination, change behind the fresh culture at 37 ℃ 5%CO
2Continue to cultivate 24h under the condition.
According to operation instruction, detect the Hela cell activity with cck-8, M3 is as shown in Figure 6 to the growth-inhibiting result of Hela cell after illumination.
Claims (10)
1. amphipathic chitose derivative, its structural formula be suc as formula shown in the I,
In the formula I, M representes hydrophobic grouping, and T representes the target ligand groups, and n is 1200 ~ 4500 number.
2. chitosan derivatives according to claim 1; It is characterized in that: said M is selected from the M group among the MCOOH, and wherein said MCOOH is selected from following at least a: Septochol, folic acid, mucinase, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine(Phe), tryptophane, tyrosine and proline(Pro).
3. chitosan derivatives according to claim 1 and 2 is characterized in that: said T is selected from the T group among the TCOOH, and said TCOOH is selected from following at least a: folic acid, Urogastron, Transferrins,iron complexes, aptamer, antibody and oligomerization polypeptide.
4. the preparation method of arbitrary said chitosan derivatives among the claim 1-3 comprises the steps:
(1) chitosan and MCOOH react under the condition of (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide existence and obtain compound shown in the formula II;
Wherein, MCOOH is selected from Septochol, folic acid, mucinase, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine(Phe), tryptophane, tyrosine and the proline(Pro) at least a; N is 1200 ~ 4500 number;
(2) compound and propylene oxide shown in the formula II react and obtain compound shown in the formula III;
(3) compound and TCOOH shown in the formula III react under the condition that (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride exists and promptly get chitosan derivatives shown in the formula I;
Wherein, TCOOH is selected from folic acid, Urogastron, Transferrins,iron complexes, aptamer, antibody and the oligomerization polypeptide at least a.
5. method according to claim 4; It is characterized in that: in the step (1), the molfraction ratio of chitosan, MCOOH, (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide is 1: (1000 ~ 4000): (500 ~ 2000): (1000 ~ 4000); The temperature of said reaction is 20 ~ 50 ℃, and the time is 15 ~ 25h.
6. according to claim 4 or 5 described methods, it is characterized in that: in the step (2), compound shown in the formula II is 1 with the molfraction ratio of propylene oxide: (10000 ~ 50000); The temperature of said reaction is 20 ~ 50 ℃, and the time is 20 ~ 30h; In the step (3), the molfraction ratio of compound shown in the formula III, T-COOH and (1-(3-dimethylamino-propyl))-3-ethyl-carbodiimide hydrochloride is 1: (3 ~ 300): the temperature of (3 ~ 300) said reaction is 20 ~ 50 ℃, and the time is 15 ~ 25h.
7. amphipathic chitose derivative micella; It prepares according to following method: arbitrary said chitosan derivatives and hydrophobic molecule among the claim 1-3 are dispersed in N; In the dinethylformamide, be added to then and promptly obtain the amphipathic chitose derivative micella that kernel is loaded with said hydrophobic molecule in the water.
8. verivate micella according to claim 7 is characterized in that: said hydrophobic molecule is hydrophobic drug and hydrophobic nano material.
9. verivate micella according to claim 8 is characterized in that: said hydrophobic drug is selected from the following substances at least a: Zorubicin, taxol and NSC 94600; Said hydrophobic nano material is selected from the following substances at least a: SPIO nano particle, carbon nanotube and carbon nanometer bugle.
Among the claim 1-3 arbitrary said amphipathic chitose derivative as the application in the pharmaceutical carrier.
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